Risk Factor For Autoimmune Diseases Research Articles

Exploring risk factors for autoimmune diseases complicated by non-hodgkin lymphoma through regulatory T cell immune-related traits: a Mendelian randomization study

BackgroundThe effect of immune cells on autoimmune diseases (ADs) complicated by non-Hodgkin lymphoma (NHL) has been widely recognized, but a causal relationship between regulatory T cell (Treg) immune traits and ADs complicated by NHL remains debated.MethodsAggregate data for 84 Treg-related immune traits were downloaded from the Genome-Wide Association Study (GWAS) catalog, and GWAS data for diffuse large B-cell lymphoma (DLBCL; n=315243), follicular lymphoma (FL; n=325831), sjögren’s syndrome (SS; n=402090), rheumatoid arthritis (RA; n=276465), dermatopolymyositis (DM; n=311640), psoriasis (n=407876), atopic dermatitis (AD; n=382254), ulcerative colitis (UC; n=411317), crohn’s disease(CD; n=411973) and systemic lupus erythematosus (SLE; n=307587) were downloaded from the FinnGen database. The inverse variance weighting (IVW) method was mainly used to infer any causal association between Treg-related immune traits and DLBCL, FL, SS, DM, RA, Psoriasis, AD, UC, CD and SLE, supplemented by MR-Egger, weighted median, simple mode, and weighted mode. Moreover, we performed sensitivity analyses to assess the validity of the causal relationships.ResultsThere was a potential genetic predisposition association identified between CD39+ CD8br AC, CD39+ CD8br % T cell, and the risk of DLBCL (OR=1.51, p<0.001; OR=1.25, p=0.001) (adjusted FDR<0.1). Genetic prediction revealed potential associations between CD25++ CD8br AC, CD28- CD25++ CD8br % T cell, CD39+ CD8br % CD8br, and the risk of FL (OR=1.13, p=0.022; OR=1.28, p=0.042; OR=0.90, p=0.016) (adjusted FDR>0.1). Furthermore, SLE and CD exhibited a genetically predicted potential association with the CD39+ CD8+ Tregs subset. SS and DM were possibly associated with an increase in the quantity of the CD4+ Tregs subset; RA may have reduced the quantity of the CD39+ CD8+ Tregs subset, although no causal relationship was identified. Sensitivity analyses supported the robustness of our findings.ConclusionsThere existed a genetically predicted potential association between the CD39+ CD8+ Tregs subset and the risk of DLBCL, while SLE and CD were genetically predicted to be potentially associated with the CD39+ CD8+ Tregs subset. The CD39+ CD8+ Tregs subset potentially aided in the clinical diagnosis and treatment of SLE or CD complicated by DLBCL.

Excess Salt Intake Activates IL-21-Dominant Autoimmune Diabetogenesis via a Salt-Regulated Ste20-Related Proline/Alanine-Rich Kinase in CD4 T Cells.

The fundamental mechanisms whereby a diet affects susceptibility to or modifies autoimmune diseases are poorly understood. Despite excess dietary salt intake acts as a risk factor for autoimmune diseases, little information exists on the impact of salt intake on type 1 diabetes. To elucidate the potential effect of high-salt intake on autoimmune diabetes, non-obese diabetic (NOD) mice were fed with a high-salt diet (HSD) or a normal-salt diet from 6 to 12 weeks of age and monitored for diabetes development. Our results revealed that HSD accelerated diabetes progression with more severe insulitis in NOD mice in a CD4+ T cell-autonomous manner when compared to NSD group. Moreover, expression of IL-21 and SPAK in splenic CD4+ T cells from HSD-fed mice was significantly upregulated. Accordingly, we generated T cell-specific SPAK knockout (CKO) NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK CKO mice when compared to HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T cell pathogenicity. Finally, pharmacological inhibition of SPAK activity using a specific SPAK inhibitor (closantel) in NOD mice ameliorated diabetogenesis, further illuminating the potential of a SPAK-targeting immunotherapeutic approach for autoimmune diabetes. Here, we illustrate that a substantial association between salt sensitivity and the functional impact of SPAK on T cell pathogenicity serves as a central player linking high-salt intake influences to immune-pathophysiology of diabetogenesis in NOD mice.

Effect of smoking on thrombotic antiphospholipid syndrome: a 10-year prospective cohort study.

Cigarette smoking is an established risk factor for autoimmune diseases. However, whether smoking plays a clear role in thrombotic antiphospholipid syndrome (TAPS) has not been determined. We aimed to investigate the effects of smoking on clinical characteristics and prognosis of TAPS. This was a prospective cohort study from 2013 to 2022. During the study period, 297 patients were diagnosed with TAPS, including 82 smokers and 215 non-smokers. After propensity score matching, 57 smokers and 57 non-smokers matched by age and sex were analysed. Overall, smokers with TAPS had more cardiovascular risk factors (CVRFs) than non-smokers, including hypertension (36.59% vs. 14.42%, P<0.001), obesity (15.85% vs. 7.44%, P=0.029), dyslipidaemia (64.63% vs. 48.37%, P=0.012), and hyperhomocysteinaemia (62.20% vs. 36.28%, P<0.001). Arterial thrombotic events were more common in smokers at diagnosis (62.20% vs. 46.05%, P=0.013), especially myocardial infarction, visceral thrombosis, and peripheral vascular thrombosis. After matching, smokers showed balanced CVRFs with non-smokers at baseline, but retained a higher prevalence of arterial thrombosis (59.65% vs. 33.33%, P=0.005), mainly distributed in cerebral vascular, cardiovascular, and retinal vascular territories. During follow-up, smokers presented a tendency for more recurrent arterial thrombosis and less recurrent venous thrombosis. Smokers had significantly poorer outcomes for organ damage with higher DIAPS (median, 2.00 vs. 1.00, P=0.008), especially in the cardiovascular (26.32% vs. 3.51%, P=0.001), gastrointestinal (15.79% vs. 1.75%, P=0.016), and ophthalmologic (10.53% vs. 00.00%, P=0.027) systems. Smoking is related to increased arterial events and poor prognosis in TAPS patients. Patients with TAPS should be fully encouraged to avoid smoking.

Association between exposure to external airborne agents and autoimmune disease

The etiology of autoimmune disease pathogeneses remains obscure, and the impact of general environmental or occupational exposure to external airborne agents (EAA) on autoimmune diseases remains understudied. This study was conducted to elucidate the association between exposure to EAA and the risk of autoimmune diseases according to exposure type. From the NHIS-NSC (2002–2019), 17,984,963 person-years were included in the data analysis. Autoimmune diseases were categorized based on the InterLymph classification. We estimated the incidence and rate ratio of autoimmune diseases according to the EAA exposure. Association between exposure and autoimmune diseases was investigated using logistic regression analysis, adjusted for potential confounders. Of the 1,082,879 participants, 86,376 (8.0%) were diagnosed with autoimmune diseases. Among these, 208 (14.1%) experienced severe exposure to EAA. Total EAA exposure was significantly associated with any autoimmune disease (OR: 1.29, 95% CI: 1.11–1.49) and organ-specific diseases (OR: 1.28, 95% CI: 1.08–1.53). Inorganic dust exposure was associated with organ-specific diseases (OR, 1.38; 95% CI: 1.01–1.81). Exposure to other dust was significantly associated with any autoimmune disease (OR: 1.35, 95% CI: 1.10–1.66), connective tissue diseases (OR: 1.43, 95% CI: 1.03–1.99), and organ-specific diseases (OR: 1.28, 95% CI: 1.00–1.65). Exposure to EAA was predominantly related to psoriasis, rheumatoid arthritis (RA), and type 1 diabetes (T1DM). We found that exposure to EAA is a potential risk factor for autoimmune diseases, especially psoriasis, RA, and T1DM. Our findings provide insight into the role of exposure to severe airborne agents in the pathogenesis of autoimmune diseases.

Exploration of the association between the single-nucleotide polymorphism of co-stimulatory system and rheumatoid arthritis.

The human leukocyte antigen (HLA) has been linked to the majority of autoimmune diseases (ADs). However, non-HLA genes may be risk factors for ADs. A number of genes encoding proteins involved in regulating T-cell and B-cell function have been identified as rheumatoid arthritis (RA) susceptibility genes. In this study, we investigated the association between RA and single-nucleotide polymorphisms (SNPs) of co-stimulatory or co-inhibitory molecules in 124 RA cases and 100 healthy controls without immune-related diseases [including tumor necrosis factor superfamily member 4 (TNFSF4), CD28, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and programmed cell death protein 1 (PDCD1)]. The results showed that there were 13 SNPs associated with RA, including rs181758110 of TNFSF4 (CC vs. CT, p = 0.038); rs3181096 of CD28 (TT vs. CC + CT, p = 0.035; CC vs. TT, p = 0.047); rs11571315 (TT vs. CT, p = 0.045), rs733618 (CC vs. TT + CT, p = 0.043), rs4553808 (AA vs. AG vs. GG, p = 0.035), rs11571316 (GG vs. AG vs. AA, p = 0.048; GG vs. AG + AA, p = 0.026; GG vs. AG, p = 0.014), rs16840252 (CC vs. CT vs. TT, p = 0.007; CC vs. CT, p = 0.011), rs5742909 (CC vs. CT vs. TT, p = 0.040), and rs11571319 of CTLA4 (GG vs. AG vs. AA, p < 0.001; GG vs. AG + AA, p = 0.048; AA vs. GG + AG, p = 0.001; GG vs. AA, p = 0.008; GG vs. AG, p ≤ 0.001); and rs10204525 (TT vs. CT + CC, p = 0.024; TT vs. CT, p = 0.021), rs2227982 (AA vs. GG, p = 0.047), rs36084323 (TT vs. CT vs. CC, p = 0.022; TT vs. CT + CC, p = 0.013; CC vs. TT + CT, p = 0.048; TT vs. CC, p = 0.008), and rs5839828 of PDCD1 (DEL vs. DEL/G vs. GG, p = 0.014; DEL vs. DEL/G + GG, p = 0.014; GG vs. DEL + DEL/G, p = 0.025; DEL vs. GG, p = 0.007). Consequently, these SNPs may play an important role in immune regulation, and further research into the role of these SNPs of immune regulatory genes in the pathogenesis of RA is required.

Clinical usefulness of anti-nuclear antibody in childhood: real-world experience at a tertiary care center : Usefulness of ANA in pediatric autoimmune diseases.

We evaluated the reasons for requesting anti-nuclear antibody (ANA) analysis in clinical practice at a tertiary center and the performance of ANA in pediatric autoimmune diseases. Patients under 18years of age who underwent ANA testing for various symptoms between 2013 and 2017 were included. We retrieved data from medical records, including demographic and clinical characteristics, diagnoses, ANA results, titers, and staining patterns. The performance assessment tools were calculated according to the ANA titer for autoimmune diseases. Risk factors for autoimmune diseases in ANA-positive patients were evaluated using logistic regression analysis. Changes in ANA titer and seroconversion were evaluated using repeated ANA analyses. A total of 3812 patients underwent ANA. Medical records of 3320 patients were obtained. The rate of ANA positivity was 27.4%. ANA was requested most frequently because of musculoskeletal findings in 1355 patients (40.8%). Juvenile idiopathic arthritis (n = 174, 20.2%) was the most common diagnosis in ANA-positive patients, followed by systemic lupus erythematosus (n = 52, 6%). For autoimmune diseases, a titer of ≥ 1:100, a sensitivity of 40.1%, and a specificity of 77.1% were observed. At a titer ≥ 1:1000, the sensitivity and specificity were 24.1% and 89%, respectively. Homogeneous staining was an additional risk factor for autoimmune diseases in ANA-positive patients by multivariate logistic regression analysis (OR [95% CI]: 4.562 [3.076-6.766], p < 0.001). Conclusion: Our results revealed that the performance of the ANA test in diagnosing autoimmune diseases in pediatric clinical practice was poor. Therefore, clinical findings should be carefully evaluated before ANA testing is performed. What is Known: • ANA can be detected in systemic autoimmune rheumatic diseases. • The diagnostic role of ANA is controversial, especially in childhood. What is New: • One in four patients who requested the ANA test had an autoimmune disease. • Less than half of patients with an autoimmune disease had ANA positivity.

Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis

Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ Tcells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate Tcell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector Tcells.

Toxoplasmosis Frequency Rate in Rheumatoid Arthritis Patients in Northeastern Iran.

Toxoplasmosis is a zoonotic disease caused by the parasite Toxo-plasma gondii, a cosmopolitan intracellular parasite. It can be a risk factor for auto-immune diseases, including rheumatoid arthritis (RA). This study was designed to investigate the possible association between serological history of T. gondii infection and defined clinical manifestation of RA in Northeast of Iran. Overall, serum samples were collected from 50 RA patients and 40 healthy controls, from Qaem Hospital in Mashhad City, northeastern Iran in 2018. Seroprevalence of T. gondii infection was determined by ELISA. The prevalence of anti -T. gondii IgG in RA patients 48% (24.50) was significantly higher than the control group 10% (4.40) (P <0.001). Erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide (anti-CCP) and (rheumatoid factor) RF levels between the RA and control groups (P <0.01). Control group were matched with patients for age, gender and living area. Given that a high correlation has been demonstrated between positivity rate of anti-T. gondii IgG and RA in Northeastern Iran, further studies will be necessary to clarify the pathogenesis of T. gondii among these patients.

The impact of the gut microbiome on extra-intestinal autoimmune diseases.

The prevalence of autoimmune diseases (ADs) worldwide has rapidly increased over the past few decades. Thus, in addition to the classical risk factors for ADs, such as genetic polymorphisms, infections and smoking, environmental triggers have been considered. Recent sequencing-based approaches have revealed that patients with extra-intestinal ADs, such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus, have distinct gut microbiota compositions compared to healthy controls. Faecal microbiota transplantation or inoculation with specific microbes in animal models of ADs support the hypothesis that alterations of gut microbiota influence autoimmune responses and disease outcome. Here, we describe the compositional and functional changes in the gut microbiota in patients with extra-intestinal AD and discuss how the gut microbiota affects immunity. Moreover, we examine how the gut microbiota might be modulated in patients with ADs as a potential preventive or therapeutic approach.

Data-Driven Mathematical Model of Apoptosis Regulation in Memory Plasma Cells.

Memory plasma cells constitutively produce copious amounts of antibodies, imposing a critical risk factor for autoimmune disease. We previously found that plasma cell survival requires secreted factors such as APRIL and direct contact to stromal cells, which act in concert to activate NF-κB- and PI3K-dependent signaling pathways to prevent cell death. However, the regulatory properties of the underlying biochemical network are confounded by the complexity of potential interaction and cross-regulation pathways. Here, based on flow-cytometric quantification of key signaling proteins in the presence or absence of the survival signals APRIL and contact to the stromal cell line ST2, we generated a quantitative model of plasma cell survival. Our model emphasizes the non-redundant nature of the two plasma cell survival signals APRIL and stromal cell contact, and highlights a requirement for differential regulation of individual caspases. The modeling approach allowed us to unify distinct data sets and derive a consistent picture of the intertwined signaling and apoptosis pathways regulating plasma cell survival.

Is Fibromyalgia Associated with Borrelia-specific T Lymphocytes?

Although fibromyalgia is a common cause of chronic musculoskeletal pain, its aetiology and pathophysiology are uncertain. It has recently been suggested that fibromyalgia symptomatology represents a T lymphocyte-mediated immune response to pathogens, which are known risk factors for autoimmune diseases. One major suggested candidate pathogen is the bacterial genus Borrelia. However, to date, this hypothesis has not been tested. The aim was to carry out the first test of this hypothesis by comparing Borrelia-specific T lymphocyte reactivity in fibromyalgia patients and matched controls. The enzyme-linked immunospot assay was used to detect T-lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen), outer surface protein (Osp) A from Borrelia burgdorferi sensu stricto, Borrelia afzelii and Borrelia garinii, native OspC plus decorin binding protein A recombinant and lymphocyte function antigen-1 (shared epitope) in 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and in 26 control subjects. The assays were carried out blind to the group status of the participants. The two groups did not differ by age, sex or ethnicity. They did not differ significantly in respect of T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) (p = 0.847), Osp mix (p = 0.709) or lymphocyte function antigen-1 (p = 0.367). This novel controlled study provides no evidence of an association between fibromyalgia and Borrelia-specific T lymphocytes.

T-Cell Aging-Associated Phenotypes in Autoimmune Disease.

The aging process causes profound restructuring of the host immune system, typically associated with declining host protection against cancer and infection. In the case of T cells, aging leads to the accumulation of a diverse set of T-cell aging-associated phenotypes (TASP), some of which have been implicated in driving tissue inflammation in autoimmune diseases. T cell aging as a risk determinant for autoimmunity is exemplified in two classical autoimmune conditions: rheumatoid arthritis (RA), a disease predominantly affecting postmenopausal women, and giant cell arteritis (GCA), an inflammatory vasculopathy exclusively occurring during the 6th–9th decade of life. Pathogenic T cells in RA emerge as a consequence of premature immune aging. They have shortening and fragility of telomeric DNA ends and instability of mitochondrial DNA. As a result, they produce a distinct profile of metabolites, disproportionally expand their endoplasmic reticulum (ER) membranes and release excess amounts of pro-inflammatory effector cytokines. Characteristically, they are tissue invasive, activate the inflammasome and die a pyroptotic death. Patients with GCA expand pathogenic CD4+ T cells due to aberrant expression of the co-stimulatory receptor NOTCH1 and the failure of the PD-1/PD-L1 immune checkpoint. In addition, GCA patients lose anti-inflammatory Treg cells, promoting tissue-destructive granulomatous vasculitis. In summary, emerging data identify T cell aging as a risk factor for autoimmune disease and directly link TASPs to the breakdown of T cell tolerance and T-cell-induced tissue inflammation.

Immune-mediated thrombotic thrombocytopenic purpura and susceptible HLA alleles

Thrombotic thrombocytopenic purpura (TTP) is an extremely rare and fatal thrombotic disorder characterized by impaired enzyme activity of von Willebrand factor cleaving protease, also known as ADAMTS13. Immune-mediated TTP (iTTP) is an acquired form of TTP caused by the production of auto-antibodies against ADAMTS13. The pathophysiology of autoimmune disorders is multifactorial, with several human leukocyte antigen (HLA) alleles identified as a genetic risk factor for autoimmune diseases known as susceptible HLA. In the early 2010s, three distinct European groups revealed that DRB1*11 is one of the most susceptible alleles in acquiring iTTP among Caucasians based on HLA typing data. Several in silico predictions for allele-restricted ADAMTS13 epitopes against T cells are made in this context, followed by an in vitro validation employing mass spectrometry using eluted peptides and T-cell assays. However, similar analyses in a genetically distinct Japanese population have not yet been conducted. We used next-generation sequencing to perform HLA typing for 52 Japanese patients with iTTP from 19 institutes. Our detailed analysis revealed that the specific allele DRB1*08:03 was identified as a genetic risk factor for iTTP in Japanese patients, but there were no statistically significant differences in the allele frequency of DRB1*11 between iTTP and healthy controls.

Central obesity in school-aged children increases the likelihood of developing paediatric autoimmune diseases.

SummaryBackgroundThe incidences of both paediatric obesity and autoimmune diseases have been increasing, but their relationship with one another is unclear.ObjectiveTo determine whether obesity or particular dietary patterns in school‐aged children are potential risk factors for autoimmune diseases during adolescence.MethodsThis matched case–control study included 525 children, followed up from a median age of 11.3 to 16.7 years. Of them, 105 children received primary autoimmune diagnoses (diabetes, thyroiditis, arthritis, or inflammatory bowel diseases) after baseline and generated the case group. Four children with matching age, sex, and residential area generated the control group of 420 children. At baseline, age‐ and sex‐specific body mass index categories were acquired and waist‐to‐height ratio (WHTR) was calculated. Central obesity was present when WHTR ≥0.5. Dietary patterns were analysed using a food frequency questionnaire (FFQ).ResultsSchool‐aged children with central obesity were 2.11 (OR, 95% CI 1.11–3.98) times more likely to develop autoimmune diseases before age of 19 years than those without central obesity. Being overweight was not related to the onset of these diseases (OR 1.60, 95% CI 0.89–2.87, nor were dietary patterns.ConclusionCentral obesity in school‐aged children was related to the development of autoimmune diseases, while being overweight and dietary patterns were not.

Association of the rs17250932, rs4794067 and rs2240017 polymorphism in the TBX21 gene with autoimmune diseases: a meta-analysis

Objective: To systematically evaluate the association between TBX21 gene polymorphisms (rs17250932, rs2240017, and rs4794067) and the risk of autoimmune diseases in Asian populations.Methods: The Medline, Web of Science, and Chinese Biomedical Literature Database were used to retrieve eligible studies that were published before July 2020. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the dominant model, heterozygote contrast model, and allelic contrast model. Publication bias was evaluated using contour-enhanced funnel plots and Egger’s regression test. Sensitivity analysis was conducted to assess the robustness of this meta-analysis.Results: A total of 12 eligible studies including 3834 patients and 4824 healthy controls were recruited in this meta-analysis. The pooled data demonstrated that TBX21 rs2240017 and rs4794067 polymorphisms are significantly associated with the risk of autoimmune diseases in Asian populations in allelic contrast model (OR: 1.456, 95% CI: 1.131–1.875, p=0.004; OR: 0.766, 95% CI: 0.615–0.954, p=0.017), heterozygote comparison model (OR: 1.647, 95% CI: 1.239–2.189, p=0.001; OR: 0.796, 95% CI: 0.634–0.999, p=0.049), and dominant mode (OR: 1.572, 95% CI: 1.194–2.071, p=0.004; OR: 0.767, 95% CI: 0.607–0.970, p=0.027). The G allele of rs2240017 may be a risk factor for autoimmune diseases and the T allele of rs4794067 may increase the risk of autoimmune diseases. However, we failed to find evidence of the association between TBX21 rs17250932 polymorphism and susceptibility to autoimmune diseases. No publication bias was found in this meta-analysis.Conclusions: This meta-analysis indicated that TBX21 rs2240017 and rs4794067 polymorphisms confer susceptibility to autoimmune diseases, but not rs17250932.

Can altered colostrum miRNA expression profile after cesarean delivery be a risk factor for autoimmune diseases?

The cesarean section (CS) rate has increased significantly in North America, Western Europe, and Latin America. However, it has been reported that the incidence of inflammatory and autoimmune diseases such as asthma and type 1 diabetes increased in parallel with CS in these countries. Our aim was to investigate the expression level of miRNAs associated with inflammatory response and autoimmune diseases in colostrum samples and contribute to elucidating the role of CS in the pathogenesis of immune system-related diseases. Colostrum samples were taken from voluntary mothers who had 40 normal and 50 cesarean births. miRNAs were extracted from colostrums and detected to miRNA expression profiling (eighty-four miRNAs) by quantitative real-time PCR with the Fluidigm integrated microfluidic circuit technology. There was a statistically significant change in the expression levels of 17 miRNAs in the colostrums of mothers who had normal and cesarean delivery (p<.05), and all of miRNAs were upregulated in the colostrums of mothers who have had cesarean delivery. Our best knowledge is that the study we conducted was the first to investigate the effect of delivery method (CS or normal) on the miRNA profile of colostrum. Cesarean delivery is a potential risk factor for inflammatory and immune system-related diseases in children due to dysregulation in miRNA expression.

Association of the rs17250932, rs4794067 and rs2240017 polymorphism in the TBX21 gene with autoimmune diseases

Objective: To evaluate systematically the association between TBX21 gene polymorphisms (rs17250932, rs2240017, and rs4794067) and the risk of autoimmune diseases in Asian populations. Methods: The Medline, Web of Science, and Chinese Biomedical Literature Database were used to retrieve eligible studies that were published before July 2020. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by using the dominant model, heterozygote contrast model, and allelic contrast model. Publication bias was evaluated using contour-enhanced funnel plots and Egger’s regression test. Sensitivity analysis was conducted to assess the robustness of this meta-analysis.Results: A total of 12 eligible studies, including 3834 patients and 4824 healthy controls, were recruited in this meta-analysis. The pooled data demonstrated that TBX21 rs2240017 and rs4794067 polymorphisms were significantly associated with the risk of autoimmune diseases in Asian populations in allelic contrast model (OR: 1.456, 95% CI: 1.131–1.875, P = 0.004; OR: 0.766, 95% CI: 0.615–0.954, P = 0.017), heterozygote comparison model (OR: 1.647, 95% CI: 1.239–2.189, P = 0.001; OR: 0.796, 95% CI: 0.634–0.999, P = 0.049), and dominant model (OR: 1.572, 95% CI: 1.194–2.071, P = 0.004; OR: 0.767, 95% CI: 0.607–0.970, P = 0.027). The G allele of rs2240017 may be a risk factor for autoimmune diseases, and the T allele of rs4794067 may increase the risk of autoimmune diseases. However, we failed to find evidence of the association between TBX21 rs17250932 polymorphism and susceptibility to autoimmune diseases. No publication bias was established in this meta-analysis.Conclusion: This meta-analysis indicated that TBX21 rs2240017 and rs4794067 polymorphism confer susceptibility to autoimmune diseases, but not rs17250932.

Perinatal risk factors for pediatric onset type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis, and inflammatory bowel diseases

Type 1 diabetes mellitus (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) are common pediatric autoimmune diseases with unknown risk factors. Using nationwide registers, we searched for their perinatal risk factors. Our study followed up 11,407 children (born 2000–2005) for a median of 16.6 years (from birth to 2018). Of them, 2.15% received primary diagnosis and 0.08% also secondary: 0.89% had DM, 0.60% had AIT, 0.48% had JIA, and 0.25% had IBD. The incidences per 100,000 children/year were 106.1 for DM, 46.0 for AIT, 55.0 for JIA, and 23.7 for IBD. There were more preterm births (< 37 weeks) among children with studied autoimmune diseases compared with the rest of the cohort (8.6% vs. 5.3%, p = 0.035). Among those born preterm, children with studied autoimmune diseases received more postnatal antibiotics compared with other preterm children in the cohort (47.6% vs. 27.7%, p = 0.046). Children with IBD were born to older mothers compared with those without studied diagnoses (33.0 vs 30.2, p = 0.004).Conclusion: Preterm birth was a shared risk factor for autoimmune diseases in our study, especially when combined with postnatal antibiotic treatments. High maternal age was associated with IBD.What is Known:• Type 1 diabetes (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) are common pediatric autoimmune diseases• It is unclear whether these diseases have shared risk factors, since there are no previous simultaneous epidemiological nor follow-up studies on them in one cohort What is New:• Preterm births were more common in children with DM, AIT, JIA, or IBD compared with other children in the cohort, and preterm children who developed these diseases recieved more postnatal antibiotics compared with other preterm children• High maternal age was associated with IBD

Multi-color Molecular Visualization of Signaling Proteins Reveals How C-Terminal Src Kinase Nanoclusters Regulate T Cell Receptor Activation

Elucidating the mechanisms that controlled Tcell activation requires visualization of the spatial organization of multiple proteins on the submicron scale. Here, we use stoichiometrically accurate, multiplexed, single-molecule super-resolution microscopy (DNA-PAINT) to image the nanoscale spatial architecture of the primary inhibitor of the Tcell signaling pathway, Csk, and two binding partners implicated in its membrane association, PAG and TRAF3. Combined with a newly developed co-clustering analysis framework, we find that Csk forms nanoscale clusters proximal to the plasma membrane that are lost post-stimulation and are re-recruited at later time points. Unexpectedly, these clusters do not co-localize with PAG at the membrane but instead provide a ready pool of monomers to downregulate signaling. By generating CRISPR-Cas9 knockout Tcells, our data also identify that a major risk factor for autoimmune diseases, the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus, is essential for Csk nanocluster re-recruitment and for maintenance of the synaptic PAG population.

Association between traffic-related air pollution and hospital readmissions for rheumatoid arthritis in Hefei, China: A time-series study

Air pollution is an important risk factor for autoimmune diseases, but its association with the recurrence of rheumatoid arthritis (RA) remains unclear so far. This study aimed to investigate the short-term association between traffic-related air pollutants and hospital readmissions for RA in Hefei, China. Data on daily hospital readmissions for RA and traffic-related air pollutants, including particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), and carbon monoxide (CO), from 2014 to 2018 were retrieved. A time-series approach using generalized linear regression model was employed. The analysis was further stratified by sex, age and season. A total of 1153 readmissions for RA were reported during the study period. A significant association between high-concentration PM2.5 (90th percentile) and RA readmissions was observed on lag1 (relative risk (RR) = 1.09, 95% confidence interval (CI): 1.01–1.19) and lasted until lag3 (RR = 1.06, 95%CI: 1.01–1.12). From lag2 to lag5, high-concentration NO2 (90th percentile) was associated with increased risk of RA readmissions, with the highest RR observed at lag 4 (1.11, 95%CI: 1.05–1.17). Stratified analyses indicated that females and the elderly appeared to be more vulnerable to high-concentration PM2.5 and NO2 exposure. High-concentration PM2.5 and NO2 in cold seasons were consistently significantly associated with increased risk of RA readmissions. Exposure to high-concentration PM2.5 and NO2 was associated with increased risk of RA readmissions. Protective measures against the exposure to high-concentration PM2.5 and NO2 should be taken to reduce the recurrence risk in RA patients, especially in females, the elderly and during cold seasons.